Going, Going, Gone… Part 3

The Urgent Need for a Brain Centered Approach to Geroprotection for Cryonicists

WHAT ABOUT THE SINGULARITY AND OUR IMMINENT RESCUE BY ADVANCES IN GERONTOLOGY?

Figure 19: Putative technological timeline for the development of technologies now thought to be required to rescue patients from cryopreservation. This timeline assumes optimistic but reasonable dates for the development of the required technologies. If this timeline is considered realistic, then maturation of the technologies required to extend lifespan indefinitely for most people now living who are aged 30 or older will not be developed with sufficient rapidity to prevent their being cryopreserved. The times for these events were culled from predictions made within the last by experts in the respective areas as obtained from peer-reviewed articles in a wide range of scientific journals. This graphic compilation and the placement on the timeline are by Mike Darwin, October, 2010.

A common response to this problem in the Cryonicist/Immortalist/Transhumanist community is to invoke the ‘coming of the Singularity,’ a near future time when societal, scientific, and economic change is hypothesized to be so fast we cannot even imagine what will happen from our present perspective, and when humanity will become ‘posthumanity.’118 Unfortunately, predicting with precision when the Singularity will happen (or even if it will happen at all) is likely to be about as accurate and reliable as predicting when the San Andreas fault will rupture, and as a consequence, when those of us living in Southern California will experience ‘The Big One.’119 Two generations have come and gone since seismologists first began warning Californians that the Big One was imminent: inevitable yes, but imminent – that’s a vague word when it comes to predicting the future – whether in the case of earthquakes – or technological advances. A careful examination of the time course of the various technological developments required for practical biological immortality, or even for dramatic life extension, as illustrated in Figure 19, gives no grounds for optimism about near-term rescue from senescence.

Beyond analyses like those in Figure 19, there are lots of more mundane reasons why technologies do not develop at anywhere near the rapidity we (or even the experts) think they will. Half a century ago, at the dawn of the ‘Atomic Age,’ there were confident predictions that nuclear power plants would be everywhere, and that ultra-rapid transcontinental atomic-powered trains would be a reality. The fact is that both of these developments were eminently practical – no fundamental technological advances were required. They didn’t happen because there were hidden real or perceived costs in nuclear energy – costs that were deemed so great that the development of these technologies has been stalled for half a century.120,121 The enabling technologies for the definitive treatment of aging, such as genetic engineering, stem cell therapy, and nanotechnology, are vastly more problematic and fraught with hazards than was nuclear power and, as a consequence, it is prudent to anticipate that there will be delays and unexpected costs in their implementation.122-124

Figure 20: Nuclear energy, known as atomic power in the middle of the last century, has been stalled in technological limbo as a result of difficult and largely unanticipated problems associated with it, such as spent fuel disposal, vulnerability to terrorist attacks, and the potential for accidental, uncontrolled release of radioactive materials into the environment.

In addition to the socially obnoxious or technologically hazardous aspects of life extension-enabling technologies, there is also the issue of paying for the enormous cost of their safe and responsible development. 1/2MT, coupled with irresponsible global fiscal policy, has put an enormous and inescapable strain on the economies of the developed world for the foreseeable future. Without doubt, one of the best arguments for radical life extension is the high cost of caring for senescent individuals.

Figure21: Health care costs over the course of human life span are clustered near the end of life, with 2/3rds of all health care dollars being expended in the last two decades of life.

Figure 21 shows how aging rapidly escalates the cost of healthcare near the end of life. As a result of mean life span extension due to 1/2MT, the cost of caring for an increasingly elderly, nonproductive, and ultimately moribund population will rapidly become astronomical, if not altogether unsupportable. The hard reality of this can be seen in Figure 22, which shows the cost of health care for Americans as function of time and a percentage of the Gross Domestic Product (GDP). Thus, the irony is that people who take good care of their health and ‘stay healthy’ actually incur greater health care costs than do those who fail to do so – extension of life span using 1/2MT carries a high cost, indeed.125

Figure 22: US healthcare costs projected to 2015 as a percentage of the GDP.

Currently, health care consumes ~16% of the GDP, and within 5 years healthcare costs will be in the range of 22% of the GDP,126 an amount that is not considered sustainable by economists of any ideological or political stripe. Nor is it conceivable that increases in productivity due to technological advance will serve to bail us out of this fix, or otherwise even partially offset these staggering costs. It is already too late to rescue the individuals who will be generating these expenses (and in fact are generating them now) from senescence. A practical consequence of this will be that money to pay for the research and development of the enabling technologies to slow, prevent, or reverse age associated morbidity will also likely be delayed or altogether absent. These truly unprecedented and frightening costs associated with modest life span extension as a result of 1/2MT will undoubtedly have serious societal implications, as well.127 While it is impossible to predict the future in this regard, it is quite conceivable that there will be a backlash against biomedicine as a result of the hard decisions that will be required, and the shortages both in medical care, and in basic resources that are likely to result.

100 BILLION NEURONS AND COUNTING – DOWN

Figure 23: Left, decline in accommodation (in diopters) as a result of aging: maximal and minimal accommodative amplitudes as a function of age as measured by the ‘push up’ technique in 150 human subjects (Duane 1912) and loss of close accommodation versus decrease in gray matter with age.

As previously noted, the loss of neurons and raw cognitive capability appears to be linear and closely correlated with the age-associated loss of function in other structures/systems that have little or no provision for maintenance during the course of the individual’s life. Loss of close accommodation, also known as presbyopia, occurs in all people who live to age 50 or beyond. Presbyopia results primarily from stiffening of the crystalline lens of the eye due to cross linkage, denaturation, and other damage to the crystallins, the class of proteins that gives the lens its unique optical properties.[1] Degradation of the crystallins, along with other age-associated changes, is the reason people middle-aged and older require reading glasses; the lenses of their eyes are no longer able to focus, or to accommodate sufficiently, to allow for close-up vision.128,129

The nucleus of the lens is compromised of fibers that are derived from cells produced during embryogenesis, which become engorged with crystalline proteins and then experience loss of both the cell nuclei, as well as the other intracellular organelles. These fibers are thus acellular and have no internal machinery for maintaining or replacing the crystallins. Some secondary lens fibers are produced during adult life, but the optical ‘core’ of the lens, the nucleus, consists of fibers that are nonviable and experience little or no protein turnover following infancy.

I’ve plotted the loss of close accommodation against the loss of gray matter in Figure 23. This is a useful comparison, because when close accommodation drops below 3 diopters of true accommodation, it can no longer be ignored, and reading glasses or other corrections to vision become necessary. Because the decay in close accommodation leads the loss of cerebral gray matter, and approximates the beginning of the steepest period of decline in white matter integrity, it may be used as a personal (and near impossible to ignore) indicator of deterioration in cognitive function. It is also almost certain that the progressive, lifelong stiffening of the lens, and the similarly progressive lifelong decline in gray matter volume (beginning at ~ 4-8 years of age) reflect absence of ‘maintenance programming’; in other words, there was insufficient evolutionary pressure to provide for ongoing housekeeping to maintain viability, or to replace damaged cells/structures in these organs. Neurons do not typically divide in mature mammals, and the lens crystallins, which comprise the lens optical fibers, are not replaced after they are laid down during fetal development, or at latest, in infancy or early childhood. The anatomical consideration which underlies this fact is that because the lens capsule completely encloses the lens, the lack of vascularization prevents large scale transport of structural nutrients into the body of the lens to allow for replacement or remodeling of degraded lenticular fibers.130

The crystallins derive their carbon-14 (14C) content from atmospheric carbon dioxide (via ingested vegetation[2]) and in this way share a feature in common with plant life.131 Perhaps one of the few redeeming benefits of the atmospheric testing of atomic weapons during the 1950s and 60s is that it resulted in a large pulse of atmospheric 14C, which subsequently found its way into developing fetuses in gestation at this time. This allows for carbon dating of lens crystallins by comparing the 14C concentration of the lens crystallins to the ‘bomb pulse’ of 14C release that occurred during the era of atmospheric nuclear weapons testing, using tree rings from the same period as a reference. As it turns out, 14C concentrations fluctuated distinctively year by year with the number of open air tests, and this has allowed for precision dating of lens crystallin proteins. The results of these studies have proved conclusively that almost all lens crystallins are elaborated during fetal development, with only miniscule (and steadily decreasing) additional synthesis over the course of life.131

Far more importantly, this technique has also been applied to the nuclear DNA of human brain neurons, with careful control for local variations in 14C levels, as well as excellent study design to exclude any possible contribution to the 14C of neuronal DNA via DNA methylation. The result of this study has demonstrated conclusively that there is essentially no neuronal cell division in the cerebral cortex of humans after the perinatal period.132 In the case of both neurons and glial cells, the brain cells that we are born with are all that we will have for the remainder of our lives. While neuron components such as cell membranes, organelles, and vesicles undergo dynamic molecular turnover, neuronal and most glial cell DNA, remain atomically unaltered throughout life. The stunning conclusion to be drawn from this research is that the very atoms that comprise our neuronal DNA at, or shortly after birth, are the same ones that we will die or enter cryopreservation with!133

The implications of this cutting edge research for cryonicists who wish to avoid the neurocognitive devastation inflicted as a consequence of aging are obvious, and need not be belabored here. Unfortunately, mature, clinically available, and FDA-approved therapies to slow or halt brain cell loss are a decade, and likely closer to two decades, away. And when clinical application does come, it will likely be only for the most serious disease states, such as AD, Huntington’s Disease (HD), and Amyotrophic Lateral Sclerosis (ALS). Even in these conditions, access to treatment may be limited by many factors, including high cost and government regulation. Thus, for many of us, even another decade of waiting will be too long.

So what are we to do? There are, encouragingly, many technical approaches to slowing and even to achieving dramatic reversal of cerebral atrophy in aging – none of which call for exotic and invasive procedures such as implantation of stem cells or genetically modified cells into the brain (procedures which also carry great risk of complications, as well as likely unaffordable costs). As hinted at in the previous discussion here of the pleiotropic effects of many of the antidepressants, there has been a very recent explosion of insights that would seem to allow for sophisticated pharmacological manipulations to reduce the loss of brain cell mass and cortical neurons. There is also the less certain prospect of inducing genuine (but limited) CNS regeneration by systemically administered drug treatment. These are topics I will explore in detail in a forthcoming article. The issue at hand here and now is: what are the organizational and strategic approaches that can, and indeed arguably must, be implemented to extend our lives and preserve our cognitive function, NOW.

AN URGENT LESSON FROM THE AIDS EPIDEMIC

Figure 24:The heart of the gay Castro District, much as it looked in 1981 when I was in San Francisco, and AIDS was just beginning.

One of the hardest things for people to understand is that it is possible to do good, without doing good enough; and nowhere is this more the case than in medical research.

In 1981, the carefree and hedonistic place that was the Castro District in San Francisco began to sprout signs in the shop windows along Castro Street showing pictures of peculiar lesions on the skin of young gay men.

Those lesions were Kaposi’s sarcoma (KS) and the puzzle was that this skin cancer, which was almost exclusively a disease of elderly Mediterranean Jewish men, was now appearing on young urban gay men.134 It was a slow growing cancer in the elderly Mediterranean Jewish men – but not in the young gay of men of ‘the Castro’ – in these men it was an aggressive and rapidly fatal disease. The new disease had a tentative name: Gay Related Immunodeficiency (GRID), and it soon became apparent that KS, and an unusual and formerly rare type of pneumonia (Pneumocystis carinii pneumonia (PCP)), were just the two most common presentations of what was soon to become a terrifying and lethal epidemic.135 Within a short time it would become apparent that GRID was not confined to homosexual men, as cases surfaced in hemophiliacs, and shortly thereafter in Haitian immigrants to the US. The disease got a new name: Acquired Immunodeficiency Syndrome (AIDS).136

Figure 25: Photographs of formerly healthy young men began to appear on handmade placards placed in the windows of pharmacies and other businesses on Castro Street, showing the disgusting and terrifying lesions of Kaposi’s sarcoma in mid- to late 1981 and urging immediate medical attention.

AIDS was an utterly mysterious disease, and as it would turn out, a surprisingly exotic one. Nothing in the history of infectious disease provided any precedent. For two years there was not even the barest clue as to what the etiologic agent might be. Speculation raged, with some taking the position it was due to chemically induced damage to the immune system from a combination of recreational drugs, including inhaled nitrates (‘Poppers’).137 In the midst of the uncertainty, one thing was certain – AIDS was a uniformly lethal disease, and a lot of gay men were infected with it. Still, it was not until ~2 years after the epidemic began that the terror began to become more or less universal amongst urban gay men. Universal terror required that most of the target population know at least one person who was dead or dying of AIDS. That point was reached by July of 1982, when a total of 452 cases, from 23 states, had been reported to the Centers for Disease Control in Atlanta, GA (CDC) and certainly by November of 1982 when that number had jumped to 716 cases.138 What happened next was arguably more amazing than the disease itself.

For the first time history, an utterly lethal (and gruesome) disease was targeting a small, relatively affluent minority that was both young and marginalized. These men also comprised a combination of male and female behavioral characteristics that would prove invaluable in shaping their response. Being male, they had the testosterone fueled aggressiveness of straight men, while being gay conferred on them the ‘feminine’ traits of verbal fluency, expertise in the arts, the service industries, and communications. Dying young men with no wife and children to distract them, and with time on their hands as death stalked them, became angry and radicalized. Indeed, the latter two ingredients were already in place as a consequence of their outsider and often vilified status as homosexuals, in a ghettoized and politicized urban environment. The gay rights movement had already set the stage for what was to come.

Figure 27:Radicalization lead to in-your-face and confrontation demonstrations that commanded the attention of the media, the political infrastructure, and most importantly, other gay men with substantial talents and energy, as well financial resources to bring to bear on the problem.

By 1983 demonstrations, peaceful and otherwise, had begun, and those men who found themselves or loved ones dying of AIDS decided to take both research and treatment into their own hands. Broadly, this effort took two forms: intense lobbying and application of pressure within the system to obtain government money at every level to support research and provide care for the dying, and the creation of the ‘AIDS Underground’: a guerrilla effort to find or to develop treatments that would do anything to improve the situation for those ill with or dying of the disease. Those efforts ranged from finding more effective ways to manage symptoms, to a full blown effort to find a definitive cure. Importantly, any advance in treating the illness and extending the lives of patients suffering from it, was the subject of underground research efforts.

Almost from the start, this effort exhibited a surprising degree of coherence and organization, probably because it sprung from underground newsletters, published by well- organized and detail-oriented personalities, exploring novel treatments and explaining how to manufacture the molecules – or smuggle them into the US. A fascinating and heart-rending account of the AIDS underground is given in the book One Boy at War: My Life in the AIDS Underground by Paul Sergios (ISBN-10: 0679418393).139

Very quickly, gay physicians and scientists began the systematic evaluation of putative compounds to cure, slow the advance of, or even just to treat the various illnesses – from PCP to opportunistic intestinal parasites. From these efforts sprang many useful treatments, including two of the first truly effective antiretrovirals, Dideoxyinosine (DDI) and dideoxycytidine (DDC), inhaled aerosolized pentamadine as a prophylaxis for PCP, and several non-FDA approved antibiotics for the relentless (and lethal) diarrhea caused by cryptosporidium. Given the small size, marginalized, and minority status of the affected population, truly staggering amounts of money were raised and funneled into precisely targeted research efforts aimed not just at ‘finding a cure’ but at finding effective treatments that would extend the lives of dying men long enough to reach a cure – a completely new idea at the time. In this effort, the gay community was astonishingly effective. They succeeded in redirecting government and private money (completely out of proportion to other healthcare priorities) to mechanistic and empirical drug research. They forced restructuring of Federal (US-FDA) drug approval process for HIV drugs, and they radically altered public perception of and attitude towards the disease by using leverage in the entertainment and publishing industries, where they had special entre. As someone who was involved in this AIDS Underground effort, I can attest to its effectiveness, and I personally know of at least two people who were actively dying of AIDS, who are still alive today because they received underground treatments which permitted then to survive until the advent of the protease inhibitor drugs, and the emergence of Highly Active Antiretroviral Therapy (HAART).

AN EXTRAORDINARY AND UNPRECEDENTED RECORD OF ACHIEVEMENT

These men were, by and large, non-scientists, though they had the extraordinary good sense to seek out and find gay men who were scientists, as well as members of the heterosexual scientific establishment who understood their research priorities and who were willing to spend the money raised not as they would have perhaps chosen, but rather how the men who had raised it wanted it to be spent.

While most involved understood the need to undertake complex, long-term mechanistic research in order to understand the pathophysiology and natural history of the etiological agent, that research was in no way to take a back seat to finding effective treatments for the opportunistic infections, AIDS wasting syndrome, and other ancillary diseases that were the proximate cause of the loss of lives for the majority of the men dying from the illness.

Additionally, basic mechanism studies were to be prioritized, and focused not on niche-type research to explore an isolated signaling mechanism, or an observed change, say, in cell morphology, but rather to fund projects that would return insights leading to almost immediate improvement in treatments. A global high priority was to identify and characterize the etiologic agent; and the gay AIDS research community, realizing that the US government was spending tens of millions of dollars on this effort, wisely chose to put their money into the hands of a scientist, Luc Montagnier, with the best track record for this kind of research, who was working at an institution that was sensitive to their priorities and concerns: The Institut Pasteur, in Paris, France. In this approach they were wholly justified, and the Institut quickly isolated the HIV virus as the causative agent of AIDS – leading to the sad spectacle of the US CDC, in the person of Robert Gallo, subsequently trying to usurp credit for this discovery.140

So, let us pause here and do a recap of what happened in the case of AIDS between 1981 and the time the causative organism was identified and a diagnostic test developed:

1981: The Disease is medically identified with fewer than 50 cases reported. This identification took place because a gay physician, Joel Weisman (a DO with a practice of almost exclusively gay men working Los Angeles), noticed unusual symptoms in his patients and began a collaboration with world-renowned UCLA immunologist Michael Gottlieb, leading to publication of the first article on GRID in the New England Journal of Medicine that same year.141

1982: Radicalization, and ultimately ‘militarization,’ of a small, but vocal and increasingly powerful cadre of men who became organized and who used a variety of directly confrontation attacks on the scientific, regulatory, and government infrastructure of the US – including confrontations with the President of the United States and the Catholic Church. Grass roots efforts were also begun to raise money and create NGOs to further a community-determined and community-based approach to research.142,143, 144, 145

1982-1983: Underground experimentation with a wide range of non-FDA approved treatments began, initially disseminated by clandestine publications such as AIDS Treatment News and Notes From the AIDS Underground which was followed almost immediately by the creation of People With AIDS (PWA) ‘AIDS Buyers Clubs’ to make unapproved medications available to ill and dying gay men.146, 147

The disease was also identified as almost certainly being due to a transmissible infectious agent.

Figure 28:The HIV virus was identified and characterized, and an antibody test developed in an unprecedentedly short period of time.

1983-1985: The Etiologic agent, an exotic and heretofore completely unknown type of retrovirus, was identified and molecularly characterized148,149, (and within less than 4 years of the identification of the epidemic, a highly reliable antibody test was tested, validated, licensed and put into universal clinical application.150, 151, 152, 153 Most of the basic research to achieve these ends was funded by NGOs, industry, and other non-US government sources, such as the Institut Pasteur.

1987: The first (marginally) effective therapeutic drug approved (AZT): zidovudine (AZT),154, 155 was introduced despite very limited effectiveness and high toxicity over the vociferous objection of the FDA, and other regulatory bodies; as well as a majority of the physicians who comprised the government-funded AIDS research community.156,157 This unprecedented exception in FDA procedures and protocol resulted almost completely from political and financial pressures brought to bear by gay AIDS activists, such as ACTUP.158,159

1987-1995: The AIDS Underground continues aggressive and largely rationally self-experimentation to find treatments and a cure.160 Compound Q is made available through underground Buyer’s’ Clubs161 and subsequently shown to be worthless (and indeed harmful) as are many other putative treatments.162 Two effective antiretrovirals are identified and put into underground use,163,164,165 and a plethora of drugs, of varying degrees of effectiveness, are identified and put into clinical use to treat a wide range of AIDS complications, such as AIDS wasting syndrome,166 Mycoplasm avians intracellularae (MAI), CMV retinopathy, PCP pneumonia, cryptosporidium,167 and a variety of other bacterial and micro-parasite infections refractory to drugs available in the US (then or now).168

Figure 29:By 1994 the molecular mechanics of HIV infection were unraveled allowing the development of the protease inhibitors, converting AIDS into a treatable disease with most patients surviving long-term.

By 1993-1994 the molecular pathophysiology of HIV infection was largely elucidated,169 again due to carefully targeted funding to achieve this end and to not run off on tangents that would have provided interesting, but not particularly clinically useful insights.

1995: Highly Active Antiretroviral Therapy (HAART) was introduced leading to long-term survival for most patients with HIV/AIDS. This treatment was highly controversial, and was roundly denounced because it employed a ‘cocktail’ of drugs which only worked effectively to control the disease when used in combination.170 This presented fundamentally new problems for the FDA, since they were (and still largely are) geared only to the approval of ‘mono-drug therapy.’ In other words, each drug in the ‘cocktail’ must be shown to be safe and effective, independent of the others!

Thus, effective control of a complex and heretofore unknown type of highly lethal etiologic agent was achieved 14 years after the start of the epidemic. There is simply no precedent for this medical accomplishment, and it is only necessary to look at the sorry pace of progress, and the veritable ocean of tangential and off the mark research, funded by disease-specific NGOs, such as the American Heart Association, the American Cancer Society,171 the Muscular Dystrophy Association and countless others, to understand this.172

These unprecedented advances, in terms of both the absolute progress and the phenomenal rate at which it was achieved, were largely a result of these factors:

Excellent data sharing, no data hoarding or secrecy, and no overt or covert desire to ‘get rich’ from discoveries that would impede the rapid and complex open and honest flow of data.

Ideal interdisciplinary basic, clinician, and bench scientist interaction. The scientists developing treatments were often the same ones employing them (often on themselves) and this provided intimate and detailed feedback about adverse effects, effectiveness, or lack thereof – as well as more nuanced and effective ways of delivering the treatments being developed.175

Collaboration with big Pharma companies when required: DDI and DDC became big Pharma drugs, as did aerosolized pentamadine for PCP, and ganciclovir for CMV retinopathy.

COURAGE and the ability to understand that human experimentation, preferably by those with the most to lose and the most to gain, is the only path to the development of fast and effective therapies. Animals are not people, just as certainly as people are not animals: and while animal research can provide useful leads, and help to explicate the mechanics of both disease processes and therapies, it is no substitute for human experimentation. The increasing absence of the latter has arguably become one of the most critical elements in slowing medical progress today.

SIMILARITIES BETWEEN THE HIV EPIDEMIC IN GAY MEN AND AGING IN CRYONICISTS

Gerontology is too important to be left to the Gerontologists

-Aschwin de Wolf, February, 2011

Ar first blush, interventive gerontology and AIDS may seem nearly identical in every important way, at least in terms of a subpopulation of the people afflicted: cryonicists. Aging and the cognitive decline associated with it, which includes the progressive and relentless destruction of the very structure, the very fabric of our personal identities, is happening to all of us and it is a 100% fatal disease. What’s more, just as was the case with AIDS, aging facilitates attack of its victims by a veritable deluge of grotesque, debilitating, and dignity-robbing diseases: cancers of almost area of the body, stroke and other cardiovascular diseases, blindness from macular degeneration, and, for everyone, the disfiguring and performance robbing changes that are the core of the aging process itself. It would also be hard to find a group of people in contemporary society more marginalized or vilified than cryonicists are today.

However, the analogy with AIDS cannot be completely sustained, because the median survival rate after diagnosis of AIDS before the advent of HAART typically only ~ 6 months to 2 years. Something which added a sense of urgency most likely not shared by those effected by brain aging, including cryonicists. I suspect that the personal and cultural traits of the male gay community culture are more conducive to pursuing such an aggressive and effective course of action than are the traits of the typical cryonicist, but serious call to arms might still be successful.

Certainly it is disheartening to see projects like this one, Research Project 2010b – Microglia Stem Cells: http://www.imminst.org/Research2010B, being funded by the Immortality Institute. This study is described as aiming to “to replace non-functional microglia with new and young microglia cells derived from adult stem cells. We will inject these young microglia cells into ‘Alzheimer mice’- a model for Alzheimer’s disease. After giving the cells some time to work, we will sacrifice the mice and measure microglia activity, neurogenesis, proliferation of neuroprogenitors and plaque density in the brain. A reduction in plaque density of Alzheimer mice would be a first proof that the transplanted microglia are performing their expected function.” It is disheartening not because this isn’t important and worthwhile work, but rather because it is scientific research of the kind that is being well funded by large, well established governmental and NGO research entities, with disease-specific agendas. A quick perusal of Pubmed shows these studies (very similar in design, therapeutic mechanism, and objectives) to have been already undertaken and completed (see Appendix A). These are the very entities who have been trying (unsuccessfully) to cure cancer heart disease, muscular dystrophy and multiple sclerosis, for decades having expended billions of dollars in taxpayers’ and charitable givers’ money with little to show in the way of progress.

THE TAKE-HOME MESSAGE

Figure 30: Survival from age 25 years. Cumulative survival curve for HIV-infected individuals and general-population controls. HIV-infected individuals are divided into three calendar periods of observation. The yellow line indicates the current life expectancy of HIV infected individuals and the red line the life expectancy before HAART was developed. Lohse N, Hansen A-BE, Pedersen G, et al, Danish HIV Cohort Study. Median survival and age-specific mortality of Danish HIV-infected individuals: a comparison with the general population. In: Program and abstracts of the XVI International AIDS Conference; August 13-18, 2006; Toronto, Canada. Abstract MOPE0310. View poster: Download PDF

If “Research Project 2010b” were completed successfully in 5 years or even in 3 years, it would still produce no results that will do anything to stop the 1 per second, 85,000 per day, or ~31 million per year brain cells you and I are losing right now – not to mention the concurrent staggering loss in neuronal and glial cell mass and function. What’s more, treatments such as these are invasive, require extraordinarily skilled practitioners to deliver the therapeutic cells to the targeted areas of the brain, carry the risk of serious (surgical) adverse events, and will cost a fortune. They also will require FDA approval and the approval of the medical infrastructure for their application – an infrastructure that does not even recognize aging as a disease and is not going to do so anytime soon. This is wonderful research, but it is research of the kind that was not undertaken by AIDS activists, and that typifies why AIDS was made a controlled and highly manageable condition whilst other, far less complex and equally devastating diseases, remain untreatable. Project 2010b is Big Medicine, disease-specific research that, at least in my opinion, is one of the last places cryonicists, and others who are trying to stay alive and cognitively healthy now, should put their time, their effort, or their money into (if for no other reason than that others will do that work and do it better).

Rather, we should look to the paradigm that brought HIV/AIDS, a fundamentally new and extraordinarily complex disease, to its knees in a scant 14 years. That paradigm focuses on identifying, funding and executing projects which offer the prospect of immediate intervention that can make material differences in the clinical condition of patients (us!) in the shortest possible time. With the advent of sophisticated brain imaging technology, and indeed even using far simpler, standard clinical MRI, as well as sophisticated psychological neurocognitive testing, such as has been developed by Salthouse and his colleagues,176 it is possible, right now, to begin evaluating the large and rapidly growing pool of molecules, both singly and in combination, that have been demonstrated to slow, and in some cases reverse, both the structural and functional neurocognitive decline associated with so-called ‘healthy aging.’

Instead of the alarmingly reckless, arbitrary, and feedback-free self experimentation that is seen with great frequency on the Immortality Institute Forums, and other life extension-related list-serves, there should be a well designed and well coordinated program of both animal and human experimentation to identify pharmacological interventions that are actually proven to slow, halt, or reverse neurocognitive decline. The imaging technology and the neurocognitive testing (much of which can be administered at a distance using a PC and the Internet) that are now both available and affordable, should be immediately pressed into service to validate the efficacy, or lack thereof, of these potentially powerful therapeutic molecules. If we had nothing more sophisticated or promising than that old standby for the treatment of bipolar disorder, lithium carbonate,[3] such research would be more than justified. But there are many promising and (so far) largely adverse effect free molecules, that cry out for further animal evaluation, followed by rapid application to those of us humans willing to take the risks – risks that I believe are wholly acceptable within the context of a well designed program of self-experimentation (with careful monitoring for both efficacy, and for the emergence of adverse effects).

Twenty years ago, gay men dying in droves from a bizarre and unprecedented illness made the decision that AIDS research was too important to be left to the mainstream government and big Pharma scientists. Instead, they took personal responsibility for their plight, organized, mobilized, agitated, and struck out on their own in search not just of a cure, but for any treatment that offered the real prospect of longer life, or a reduced disease burden. They achieved amazing things, because they knew they were dying NOW, and because they also well understood that the society they were embedded in fundamentally didn’t give a damn about them – or their priorities.177 If you want graphic proof of just how miraculously effective their efforts were, all you need to do is look at Figure 30, or at mortality data from similar studies.178

We cryonicists are in exactly the same position today. The question is, are we smart enough to realize it, and courageous enough to take the necessary action?

The End

Footnotes

[1] There is currently debate over whether atrophy of the ciliary muscles is contributory to the presbyopia of aging. While atrophy of the ciliary muscles may contribute to presbyopia, there can be no question that the primary causes are changes in lens dimensions with age, age- associated changes in geometry of the zonular attachments, of the lens, and changes in the viscoelastic properties of the lens capsule and the lens crystallins; the latter resulting in increased lenticular stiffness as a result of cross linking and denaturation of lens proteins. Similarly, there has been controversy over whether the continued production of secondary lenticular fibers, resulting in forward displacement of the lens nucleus, is contributory to loss of close accommodation. While it is likely that this is indeed the case, the primary cause appears to be degradation of the lens crystallins. Bron AJ, Vrensen GF, Koretz J, Maraini G, Harding JJ. The ageing lens. Ophthalmologica. 2000 Jan-Feb;214(1):86-104. Review. PubMed PMID: 10657747.

[2] Either directly by consuming plants, or indirectly by eating animals that feed on plants, 14C is acquired from atmospheric CO2.

[3] The doses at which lithium appears to exert a positive effect on cerebral atrophy in both depression and aging appear to be below those required for treatment of frank bipolar disorder. This is important because lithium has a narrow therapeutic margin in the management of bipolar disease with the therapeutic dose being perilously close to the toxic dose. This requires frequent blood work to ensure safe serum lithium levels and thus avoid potentially life threatening complications.

147) The AIDS Epidemic in San Francisco: the medical response, 1981-1984, Volume I, an oral history conducted in 1992-1993, Regional Oral History Office, The Bancroft Library, University of California, Berkeley, 1995

21 Responses to Going, Going, Gone… Part 3

It is more likely that presbyopia is due to continued growth of the lens rather than a degradation in the lens material itself. It sort of like how cartilage in the nose and ears continues to grow indefinitely. This is easily testable. Get lenses from both old and young cadavers and measure the elasticity with nanoindentation.

The optical properties can easily be measured by spectrophotometer such as those made by Shimadzu or Agilent.

The other reason why I think degradation of the lens material is not the cause of presbyopia is that any changes in the physical properties (elasticity) should also change the optical properties (transmittance, reflectance) as well. Generally, this does not occur until cataract formation.

I’ve spent a lot of time researching this area, both in the literature and by talking directly with ophthalmologists and researchers who are ‘experts’ in this field. In my initial draft of this paper I devoted two pages to discussing the various competing theories of why loss of close accommodation occurs in aging. It was too much, and too out of context for a paper on brain aging. Broadly, three theories have been proposed to explain presbyopia:

1) Increased stiffness and other changes in the character of the lens due to a wide array of chemical changes in the lens crystallins, including cross-linking from free radicals, glycosylation, and oxidation of cysteine in lens proteins.

2) Increased lens thickness due to continued peripheral addition of lens structural elements.

3) Sarcopenia (muscle wasting) of the cilliary muscles which prevents them from adequately deforming the lens to allow for close accommodation.

It may be that all three of these mechanisms are operational, but it is clear from the latest work that the primary mechanism is chemical alterations of the lens crystallins which stiffen the lens, alter its shape (thus making it more difficult to deform) and yellow it. By the time you are my age, you will likely begin to notice a truly annoying and dangerous loss of night vision and increased glare from headlights and street lights which results primarily from yellowing of the lens as a result of the accumulation of oxidized cysteine residues.

Some good review papers are:

On the growth and internal structure of the human lens. Robert C. Augusteyn, Experimental Eye Research 90 (2010) 643e654.

I have many more papers, and while it is clear that several mechanisms are likely to be in play, the dominant one clearly seems to be alteration in lens proteins that result in stiffening of at least some lens elements causing the various focal elements within the lens to misbehave – as well as making it impossible for the lens to accommodate adequately due increased overall stiffness. — Mike Darwin

Scleral expansion surgery for presbyopia is consistent with the theory that presbyopia is caused by continued growth of the lens (and the crowding out of the cilliary muscles such that they do not work properly) and not by a change (degradation) of the lens material itself. I know about this surgery. It has been available in Mexico for some time now and is not anything I would even consider. I’m averse to any kind of eye surgery, as I am averse to any kind of surgery in general.

In any case, identifying the cause of presbyopia can be done with about one week’s worth of research using Hysitron’s nanoindenter and a spectrophotometer, made by a half dozen manufacturers.

The amount of leverage the gay community managed to obtain and utilize in such a short time gives me some hope. Neurosenescence is a bottleneck that halfway tech can’t get past. I have this one vision of a future where the elderly live and work in robotic exo-suits, hermetically sealed with automated life support and other systems carefully designed to keep them from experiencing too much stress or too little exercise.

That’s not necessarily as dystopian as it sounds. Given enough incremental improvements, it could be quite comfortable. Even memory loss could be accounted for with systems that remind you periodically of who your friends are and how to perform tasks. But the more brain volume you lose the less we can say you’ve really survived. Suppose a person lives 200 years on mobile life support — does their brain continue to shrink, or will it stop shrinking at some point?

It was an astonishing experience that shouldn’t have happened, as near as I can tell. I expected the FDA to come down like a ton of bricks, and I expected the government and Pharma to refuse to cooperate. As it was, there was surprisingly little resistance. In hindsight, I think there were many reasons for this that were opaque to me at the time. For one thing, it was just a disgusting, frightening disease that no one wanted to touch. The Feds quickly learned that they if they wanted to do enforcement they had to literally manhandle infected and dying gay men – some of whom would spit on them, bite them, or cut themselves and bleed on them. Law enforcement didn’t want to even breathe the same air…

The dying gay community was also an aesthetic elite at that time, and they were highly valued by influential people in the media and the arts. That influence provided substantial buffer and lots of money. There was also the dirty little secret that a number of very influential men in the halls of power were both homosexual and infected – and that probably acted to stay many a hand in ways we’ll never know.

Finally, the men who did this were extraordinary – exceptional not only in their desire to live, but in to the lengths they would go to in order to continue do so. I think the last was the most important. — Mike Darwin

Speaking of the timeline, forget about the quantum teleportation. This is a fantasy as a method of transport of actual physical objects (and people). The self-driving autos already exist. Google developed them and has been running them on California streets for some time. The reason why we will not have them anytime soon is because of liability. The timeline for revival of suspension patients seems about right – early to mid 22nd century. This assumes, of course, that there is enough neurostructure of these people preserved such that revival is possible. Otherwise, they’re coming back as “new” people.

Since it was a mostly “just for fun” exercise, and was also in support of the brain aging article, I didn’t go into detail about the various developments or the underlying assumptions. When I “envisage” quantum teleportation, I’m thinking of something vastly more sophisticated than can be easily imagined today – something using the principle of superposition of states. It is clearly possible to teleport tiny amounts of information from ion to ion exploiting this phenomenon: Wineland:http://tf.nist.gov/general/pdf/1926.pdf, Blatt:http://heart-c704.uibk.ac.at/publication…, Kimble: http://arxiv.org/abs/quant-ph/0702057. Whist I understand that you don’t think much of quantum computing or engineering, I think in this opinion you are likely mistaken. I’ve seen things in my travels that have given me pause, and I believe that quantum computation will not only be developed, but that it will have profound effects on our understanding of the very nature of reality. A very dated, but nonetheless excellent review of this area of endeavor is The Quest for the Quantum Computer by Julian Brown, ISBN 0-684-87004-5.

What we may have here is more of a disagreement about the criteria for when a technology is viable. An assumption in my timeline, perhaps not stated, is that the technology be USED. That means it must necessarily have overcome the numerous social, political and economic hurdles to application. For instance, xenograft transplantation is already likely to be possible – but it is not being exploited in its current imperfect state for many reasons, not the least of which are concerns over viral recombination occurring between etiologic agents in man and pig… – Mike Darwin

It seems an all but completely forgotten epoch. As far as I know , Paul Sergios’ book is the only one written on the subject. Almost all of those who were intimately involved are dead (or in a case or two, cryopreserved). That’s unfortunate, because I believe it is a useful example of what is possible.

I’ve never understood the rationale for why governments would be antipathetic to life extension drugs. The only thing that will bail out the West economically is for just such drugs to materialize, and now! As to the idea of true web security/privacy, I’m aching to know how that might be practically possible. There are two kinds of secrets: those that need to be kept for a short while (months to a decade) and those that need to be kept for a long while (decades to a century or more). The rate at which cryptography is advancing makes the latter really problematic.

On a related topic, I’m really surprised that there has been so little attention paid to fMRI for lie/truth detection. It is physically impossible to deliberately lie without that being reflected in the physiochemistry of the brain and more specifically without it inducing metabolic activity in areas not :activated under “no-lie” conditions. I find it hard to believe that, quite aside from commercial concerns like No Lie MRI, that there is not considerable effort going into perfecting and validating this technology. IMHO that will be a game changer. This is a topic I hope to see explored here in the future. — Mike Darwin

Functional MRI scanners are being developed and, yes, they will be a game changer in crime investigation. There are “activitists” who claim that fMRI represents “cruel and unusual punishment” and is analogous to torture. However, I do not see this point at all. The process involves no pain and suffering on the part of the subject and is no different in this regard than a polygraph.

I’ve never understood the rationale for why governments would be antipathetic to life extension drugs. The only thing that will bail out the West economically is for just such drugs to materialize, and now!

I’ve been saying this every chance I get on the blogosphere for nearly a decade. I always get ditsy responses like “it will cost too much”, “it disrupts family life”, “generational cycles” or other such crappola. I think a lot of peoples’ brains just don’t work properly.

As to the idea of true web security/privacy, I’m aching to know how that might be practically possible.

I don’t think there is. My attitude is that you simply do not put details of your private life on the net (e.g. social networking sites) where it will be publicly cast in concrete for next to eternity.

I’ve never understood the rationale for why governments would be antipathetic to life extension drugs. The only thing that will bail out the West economically is for just such drugs to materialize, and now!

I can venture a guess. Government is a bureaucracy. The last thing bureaucrats want is to have all of the problems solved. This eliminates the need for the bureaucracy and that is the last thing that they want.

Yes and no. I think that’s generally true of smaller, territorial issues. When I was a teenager I actively lobbied for the creation of the National Institutes of Aging. I met with both of my Reps in Indiana and I found they had a good understanding of the demographic problem that an aging and much longer lived population presented. While they both had reservations about the money a NIA would cost, and whether it would really be effective, I had no doubt that if they believed that it would work, they would have voted for it. (They may have anyway.) Today, the situation is absolutely critical and this not hyperbole. We are spending 12% of our GPD on healthcare and that will explode to over 20% in less than a decade! That isn’t sustainable. Everyone knows this. Everyone with half a brain – including at least a slim majority of Congress. If you credibly lay a program before them that would vastly extend healthy productive lifespan – even absent rejuvenation – most would bite. This is the case because it would mean that the young people today could work far longer and pay off the cost of sending their parents and grandparents to the grave.absent euthanasia or neglect and with some measure of dignity. Unfortunately, no such assurances can be given and no such program exists. — Mike Darwin

> Project 2010b is Big Medicine, disease-specific research that, at least in my opinion, is one of the last places cryonicists, and others who are trying to stay alive and cognitively healthy now, should put their time, their effort, or their money into (if for no